Millions of children worldwide are exposed to neurotoxic substances in their environment, such as arsenic, that produce potentially irreversible intellectual and behavioral impairments. Cognitive deficits, most typically measured as IQ in school children living in high-exposure areas, have been associated with higher concentrations of arsenic in drinking water, urine and hair. However, we have limited understanding of the extent to which low- level arsenic exposure is associated with children's cognitive function and behavior. This gap in knowledge limits accurate risk assessment and the communication of health risks associated with arsenic exposure. The long-term goal is to understand how low-level arsenic exposure affects neurobehavioral outcomes across childhood and adolescence, and to identify host and environmental factors (such as age, sex, genetic make- up, nutritional status, and other environmental exposures) that may modify the effects of arsenic on child cognition and behavior. The objective of the proposed study is to determine the effects of low-level arsenic exposure and arsenic methylation capacity on cognitive function and behavior in 6-7 year-old children. The central hypothesis is that within low-range of exposures, higher arsenic concentrations in water and urine (particularly higher fraction of urinary methylarsonic acid) will be associated with poorer cognition and behavior problems. The two specific aims are 1) Determine to what extent low-level arsenic exposure (<50 5g/L) is associated with neurobehavioral outcomes in first-grade children, and 2) Determine to what extent low arsenic methylation capacity impairs cognition and behavior in first-grade children exposed to As. Archived water and urine samples from an ongoing study of first-graders from Montevideo, Uruguay will be utilized to address both aims, in addition to the collection of water and urine samples from newly enrolled children. Results from extensive Neurobehavioral assessments of the children and indicators of nutritional status and neurotoxicant exposure will be employed. This approach is innovative because in contrast to previous studies, it systematically examines the effects of low-level arsenic exposure and methylation capacity on child cognition. These methodological advances will result in more accurate risk-assessment of arsenic exposure on its own and provide important data to inform the design of large, systematic investigations of these issues in the future. This research is significant in its contribution to the communication of health risks associated with arsenic exposure. Important strides toward the prevention of exposure and the development of risk-modification strategies can also be achieved once factors associated with the excretion of arsenic (methylation) are identified. Finally, the significance of this research, over the long-term, lies in its potential contribution to policies on arsenic monitoring and action levels in settings, such as the United States, where children typically experience low-level arsenic exposure. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because the characterization of the cognitive/behavioral effects of low-level arsenic exposure in children will result in more accurate communication of health risks in pediatric populations and the identification of appropriate prevention or intervention strategies. This research is relevant to the mission of the NIEHS through its contribution of fundamental knowledge that will reduce the burden of human disability by understanding environmental influences on disease development.